JP2022526942A - Use of oncolytic virus in neoadjuvant therapy for cancer - Google Patents

Abstract

The present invention relates to the use of oncolytic viruses in neoadjuvant therapy regimens for the treatment of cancer.

Description

Mutual reference of related applications This application is a US provisional patent application No. 62 / 825,929 filed on March 29, 2019, and a US provisional patent application No. 62 / filed on August 2, 2019. Claim the priority and interests of 882,013 and US Provisional Patent Application No. 62 / 898,889 filed September 11, 2019, each of which is by reference in its entirety. Incorporated herein.

Sequence Listing Reference This application includes a computer-readable sequence table. The sequence listing is A-2364-WO-PCT_SeqListing_ST25. Created on February 18, 2020. It is provided as a text file named pxt and is 15,346 bytes in size. The information in the electronic format sequence listing is incorporated herein by reference in its entirety.

Although melanoma is easy to detect early, the prognosis for patients with high-risk primary melanoma or patients with gross lymph node metastases remains inadequate. The best option for patients with higher-risk melanoma (eg, resectable melanoma) is to receive effective adjuvant therapy to reduce their chances of recurrence. Several systemic therapies have been tested as adjuvant therapies for melanoma that have benefited. In recent years, high doses of 10 mg / kg ipilimumab have shown significant improvements in recurrence-free survival and overall survival in patients with stage 3 melanoma, but at a significant cost to immune-related toxicity. The results of recent clinical trials with immunotherapy (PD-1 inhibitor) and molecular targeted therapy (BRAF inhibitor + MEK inhibitor) have improved the management of adjuvant treatment for melanoma. As the results from these trials mature, new treatment decisions such as predictive and prognostic biomarker patient selection and optimizing the management of treatments associated with adverse events, especially immune-related toxicity, are new. Problems will arise. Cancer Treat Rev. 2018 Sep; 69: 101-111. doi: 10.016 / j. ctrv. 2018.06.003. EPUB 2018 Jun 9.

Achieving pCR after neoadjuvant chemotherapy has been observed to be associated with significant improvement in disease recurrence and survival in the context of triple-negative and HER2 + breast cancer. Spring et al. , Cancer Res February 15 2019 (79) (4 Supplement) GS2-03; DOI: 10.1158 / 1538-7445. SABCS18-GS2-03. Most recently, data presented by the International Neoadjuvant Melanoma Consortium (INMC) conclude that the ability to achieve a complete pathological response correlates with improved RFS. (Menzies a et al, 2019 ASCO Annual Meeting). However, further research is still needed to assess the clinical usefulness of the incremental / tapering scheme in adjuvant setting based on the patient's neoadjuvant response.

Therefore, there is still a need for new neo-adjuvant therapy schemes (such as utilizing oncolytic viruses) that optimize neo-adjuvant therapy, first-line therapy, and adjuvant therapy within those treatment regimens. ..

Cancer Treat Rev. 2018 Sep; 69: 101-111. doi: 10.016 / j. ctrv. 2018.06.003. EPUB 2018 Jun 9 Spring et al. , Cancer Res February 15 2019 (79) (4 Supplement) GS2-03; DOI: 10.1158 / 1538-7445. SABCS18-GS2-03 Menzies a et al, 2019 ASCO Annual Meeting

The present invention comprises administering a combination of an oncolytic virus and a first checkpoint inhibitor, surgically removing any residual tumor, and administering a second checkpoint inhibitor. The first and second checkpoint inhibitors may be the same or different, relating to a method of treating cancer.

The oncolytic virus used in the present invention may be adenovirus, leovirus, measles virus, simple herpesvirus, Newcastle disease virus, Seneca virus, or vaccinia virus. In certain embodiments, the oncolytic virus is an adenovirus, leovirus, herpes simplex virus, Newcastle disease virus, or vaccinia virus. In some embodiments, the oncolytic virus is a herpes simplex virus, such as the herpes simplex virus type 1 virus (HSV-1). HSV-1 may be modified to lack the functional ICP34.5 gene, lack the functional ICP47 gene, and contain a gene encoding a heterologous gene. In some embodiments, the heterologous gene is a cytokine such as GM-CSF (eg, human GM-CSF). In certain embodiments, the oncolytic virus is tarimogene laharparepbeck, RP1, RP2, or RP3. In another particular embodiment, the oncolytic virus is tarimogene laharparepbeck.

The first and second checkpoint inhibitors used in the present invention may be independently selected from the list containing CTLA-4 blockers, PD-1 blockers, and PD-L1 blockers. In some embodiments, the CTLA-4 blocker is an anti-CTLA-4 antibody, the PD-1 blocker is an anti-PD-1 antibody, and the PD-L1 blocker is an anti-PD-L1 antibody. The CTLA-4 blocker may be ipilimumab. The PD-1 blocker may be nivolumab, pembrolizumab, CT-011, AMP-224, semiprimab, or an anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10. The PD-L1 blocker may be atezolizumab, avelumab, durvalumab, or BMS-936559.

Cancers that can be treated using the methods of the invention include melanoma, breast cancer (eg, triple negative breast cancer), kidney cancer, bladder cancer, colorectal cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, liver cancer, non-cancer. Breast cancers include skin cancers, neuroendocrine tumors, T-cell lymphomas (eg, peripherals), or cancers of unknown primary origin, pediatric solid tumors with unresectable epidermal lesions. In some embodiments, the cancer is stage 2, 3a, 3b, 3c, 3d or 41a melanoma.

The present invention also comprises a simple herpesvirus, which lacks the [1] functional ICP34.5 gene, lacks the functional ICP47 gene, and contains a gene encoding human GM-CSF, and [2] an oncolytic virus and a first. In an attachment or label with instructions to treat the cancer by administering it in combination with the checkpoint inhibitor of, surgically removing any residual tumor, and administering a second checkpoint inhibitor. Here, the first and second checkpoint inhibitors relate to a kit comprising an attachment or label, which may be the same or different. In some embodiments, the invention relates to a method of making such a kit.

The study scheme of the Amgen study 20120266, comparing the efficacy and safety of Talimogene Laharparepbeck's neoadjuvant therapy with surgery for resectable stage IIIB to IVM1a melanoma compared to surgery alone. This is a Phase 2 multicenter, randomized, open-label clinical trial evaluated. It is a Kaplan-Meier plot showing the time to progression-free survival (RFS) in a population of treatment plan (ITT) patients at 1 year. All non-R0 resections at baseline were events (ie, all relapses + all non-R0 resections). At 1 year, 33.5% of patients with Arm 1 and 21.9% of Arm 2 had no evidence of disease recurrence (HR 0.73, P = 0.048). It is a Kaplan-Meier plot showing the time to progression-free survival (RFS) in a population of treatment intention (ITT) patients at 2 years. All non-R0 resections at baseline were events (ie, all relapses + all non-R0 resections). At 2 years, 29.5% of Arm 1 patients and 16.5% of Arm 2 patients had no evidence of disease recurrence (HR 0.75, P = 0.070). A Kaplan-Meier plot representing the time to RFS in an ITT patient population that does not consider non-R0 resection at baseline as an event (1 year landmark analysis). RFS was defined as the first of local, regional, or distant recurrences of melanoma, or death due to some cause after surgery. Subjects who did not undergo surgery were considered events at baseline. At 1 year, 55.8% of patients with arm 1 and 39.3% of patients with arm 2 remained relapse-free (HR 0.63, P = 0.0024). A Kaplan-Meier plot representing the time to RFS in an ITT patient population that does not consider non-R0 resection at baseline as an event (2-year landmark analysis). RFS was defined as the first of local, regional, or distant recurrences of melanoma, or death due to some cause after surgery. Subjects who did not undergo surgery were considered events at baseline. At 2 years, 50.5% of Arm 1 patients and 30.2% of Arm 2 patients had no evidence of disease recurrence (HR 0.66, P = 0.038). It is a Kaplan-Meier plot showing the overall survival time (OS) at one year. 85.8% of Arm 2 patients were alive at the one-year landmark (HR 0.47, P = 0.078), compared to 95.9% of Arm 1 patients. It is a Kaplan-Meier plot showing the overall survival time (OS) at one year. 88.9% of Arm 1 patients and 77.4% of Arm 2 patients were alive at the two-year landmark (HR 0.49, P = 0.050). Treatment with Tarimogene Laharparepbeck tripled the CD8 + cell density in the tumor (P <0.001), resulting in a 17-unit increase in PD-L1 expression H-score in arm 1 (P <0.001). = 0.038). The CD8 + density and H-score of PD-L1 were also higher in arm 1 after treatment with Talimogene Laharparepbeck compared to arm 2 (both P <0.001). It is illustrated that the increase in CD8 + cell density in the tumor after treatment with Tarimogene Laharparepbeck in Arm 1 correlates with longer RFS (sensitivity analysis) and longer OS.

As used herein, the term "immune checkpoint inhibitor" refers to a molecule that completely or partially reduces, suppresses, interferes with, or regulates one or more checkpoint proteins. .. Checkpoint proteins regulate T cell activation or its function. Numerous checkpoint proteins such as CTLA-4 and its ligands CD80 and CD86, as well as its ligands PD-L1 and P-DL2 along with PD-1 are known (Pardol, Nature Reviews Cancer 12: 252-264, 2012). .. These proteins are involved in co-stimulating or inhibitory interactions of T cell responses. Immune checkpoint proteins control and maintain autoimmune tolerance and the duration and swing of physiological immune responses. Immune checkpoint inhibitors include or are derived from, for example, antibodies.

As used herein, the term "antibody" refers to a protein having a conventional immunoglobulin composition that includes heavy and light chains and contains variable and constant regions. For example, an antibody has a "Y-shaped" structure with two pairs of the same polypeptide chain, each pair having one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy". It can be an IgG having a chain (usually having a molecular weight of about 50-70 kDa). The antibody has a variable region and a constant region. In the IgG structure, the variable region is generally about 100-110 or more amino acids, contains three complementarity determining regions (CDRs), is primarily involved in antigen recognition, and is substantially among other antibodies that bind to different antigens. Are different. The constant region allows the antibody to recruit cells and molecules of the immune system. The variable region is made up of the N-terminal region of each light chain and heavy chain, while the constant region is made up of the C-terminal portion of each of the heavy and light chains (Janeway et al., "Structure of the Antibody". Molecular and the Immunoglobulin Genes ”, Immunobiology: The Immunosystem in Health and Disease, 4th ed. Elsevier Science ( ^Lid./Gan ).

As used herein, the terms "patient" or "subject" are used interchangeably and include, but are not limited to, human or non-human mammals such as cows, horses, dogs, sheep or cats. Means mammals. Preferably, the patient is a human.

All clinical response assessments described herein (eg, ORR, DoR, etc.) are measured by Response Evaluation Criteria in Solid Tumors (RECIST). Eisenharer EA, Therapy P, Bogaerts J, et al. New response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009; 45: 228-247, which is incorporated herein by reference in its entirety.

As used herein, "response rate" is the incidence of either a confirmed complete response or a partial response.

As used herein, "time to response" is the time from treatment to the date of the first confirmed objective response by modified RECIST.

As used herein, "response period" is the time from the first confirmed objective response to confirmed disease progression or death (whichever occurs earlier) by modified SECIST. Is.

As used herein, "progression-free survival" is the time from treatment to the date of first confirmed disease progression according to modified RECIST criteria.

As used herein, "recurrence-free survival" or "disease-free survival" is the time from treatment (surgery) to the date of first recurrence or death.

As used herein, "event-free survival" refers to one of the following from randomization: progression of disease that interferes with surgery, local or distant recurrence, or death due to some cause. It is the time until.

As used herein, "distant metastasis-free survival" or "distant disease-free survival" is the time from surgery to the first occurrence of distant metastasis.

As used herein, "survival" refers to a surviving patient and includes overall survival as well as progression-free survival. The 1-year survival rate and the 2-year survival rate refer to the KM estimator, which is the ratio of subjects who survive for 12 months or 24 months.

As used herein, "prolonging survival" refers to overall survival and / or progression-free survival in treated patients as compared to control treatment protocols such as treatment with ipilimumab alone. Refers to increasing. At least about 1 month, 2 months, 4 months, 6 months, 9 months, or at least about 1 year, or at least about 2 years, or at least about 3 years, or at least about 4 years after the start of treatment or initial diagnosis. Or monitor survival for at least about 5 years, or at least about 10 years.

As used herein, "reduce or suppress" means 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or higher. It is the ability to cause an overall reduction in. Reduction or suppression can refer to the symptoms of the disease being treated, the presence or size of metastases, or the size of the primary tumor.

Cancer can be divided into "stages" based on the progression / development of the disease. In general, stages are divided into stages 1, 2, 3 and 4 subdivided into several stages, with stage 1 indicating early stage disease and stage 4 indicating late / more advanced stage disease. .. For example, in the context of melanoma, stage 1 and 2 melanoma patients suffer from localized disease, while stage III and IV melanoma patients suffer from locally metastatic and distant metastatic disease, respectively. Patients with stage 2 melanoma who have high-risk features (such as large tumor thickness and presence of ulcers), despite being partially defined by the absence of local disease, have better features. Can have a worse prognosis than patients with primary melanoma and patients with limited potential locally metastatic disease (stage 3A). For example, patients with stage 2C melanoma have worse expected 5-year and 10-year survival rates than patients with stage 3A disease (93% and 88%, compared to 82% and 75%, respectively).

In addition, stage 3 melanoma was clinically detected for tumor thickness, ulcer status, and number of lymph nodes with the tumor (and whether these were clinically subclinical). It is divided into four subgroups based on the presence or absence of non-lymph node local metastasis. There are significant differences in prognosis across the four stage 3 subgroups, with melanoma-specific survival (MSS) after 5 years ranging from 93% of stage 3A disease to 32% of stage 3D disease. Become. Compared to MSS 5 years after stage 3A, 3B and 3C disease in the 7th edition, these proportions are very good (78%, 59% and 40% respectively), clinical decision making and patient counseling. And has a significant impact on clinical trial design.

Stage 4 melanoma has spread through the bloodstream to distant sites on the epidermis or soft tissue, distant lymph nodes, or other parts of the body such as the lungs, liver, brain, bone, or other organs such as the gastrointestinal tract. Described as melanoma. Stage 4 is further evaluated based on the site of distant metastasis. Stage 4a: Cancer has spread only to the distant epidermis and / or soft tissue site. Stage 4M1b: Cancer has spread to the lungs. Stage 4M1c: The cancer has spread to other parts of the body that do not contain the central nervous system. Stage 4M1d: Cancer has spread to the central nervous system, including the brain, spinal cord and / or cerebrospinal fluid, or the capsule of the brain and / or spinal cord.

The terms "CD8 density", "CD8 + density" or "CD8 + T cell density" refer to the number of CD8 + T cells present in a sample, eg, a tumor sample. In an exemplary embodiment, the CD8 + T cell density is the number of cells present in a sample of tumor from the subject, eg, a 1 mm ² sample (eg, punch biopsy) or a 1 mL (ie, 1 cm ³ ) sample (eg, liquid biopsy). Is. In one particular exemplary embodiment, a low CD8 + T cell density (associated with a "cold" tumor) is less than about 3000 cells per 1 mm ² or 1 mL sample, and about 2900 cells per 1 mm ² or 1 mL sample. Less than about 2800 cells per 1 mm ² or 1 mL sample, less than about 2700 cells per 1 mm ² or 1 mL sample, less than about 2600 cells per 1 mm ² or 1 mL sample, 1 mm ² or 1 mL Less than about 2500 cells per 1 mm ² or 1 mL sample, less than about 2400 cells per 1 mm ² or 1 mL sample, less than about 2300 cells per 1 mm ² or 1 mL sample, less than about 2200 cells per 1 mm 2 or 1 mL sample. Cells, less than about 2100 cells per 1 mm ² or 1 mL sample, less than about 2000 cells per 1 mm ² sample, less than about 1900 cells per 1 mm ² sample, about 1800 cells per 1 mm ² or 1 mL sample Less than about 1700 cells per 1 mm ² or 1 mL sample, less than about 1600 cells per 1 mm ² or 1 mL sample, less than about 1500 cells per 1 mm ² or 1 mL sample, 1 mm ² or 1 mL Less than about 1400 cells per 1 mm ² or 1 mL sample, less than about 1300 cells per 1 mm ² or 1 mL sample, less than about 1200 cells per 1 mm ² or 1 mL sample, less than about 1100 cells per 1 mm 2 or 1 mL sample. Cells, less than about 1000 cells per 1 mm ² or 1 mL sample, less than about 900 cells per 1 mm ² or 1 mL sample, less than about 800 cells per 1 mm ² or 1 mL sample, 1 mm ² or 1 mL sample Less than about 700 cells per, less than about 600 cells per 1 mm ² or 1 mL sample, less than about 500 cells per 1 mm ² or 1 mL sample, less than about 400 cells per 1 mm ² or 1 mL sample, Less than about 300 cells per 1 mm ² or 1 mL sample, less than about 200 cells per 1 mm ² or 1 mL sample, or less than about 100 cells per 1 mm ² or 1 mL sample. In one particular exemplary embodiment, a low CD8 + T cell density is about 3000-500 cells per 1 mm ² or 1 mL sample, about 2900-500 cells per 1 mm ² or 1 mL sample, 1 mm ² or About 2800-500 cells per 1 mL sample, about 2700-500 cells per 1 mm ² or 1 mL sample, about 2600-500 cells per 1 mm ² or 1 mL sample, about 2600-500 cells per 1 mm ² or 1 mL sample 2500-500 cells, about 2400-500 cells per 1 mm ² or 1 mL sample, about 2300-500 cells per 1 mm ² or 1 mL sample, about 2200-500 cells per 1 mm ² or 1 mL sample Cells, about 2100-500 cells per 1 mm ² or 1 mL sample, about 2000-500 cells per 1 mm ² or 1 mL sample, 1900-500 cells per 1 mm ² or 1 mL sample, 1 mm ² or About 1800-500 cells per 1 mL sample, about 1700-500 cells per 1 mm ² or 1 mL sample, about 1600-500 cells per 1 mm ² or 1 mL sample, about 1 mm ² or 1 mL sample 1500-500 cells, about 1400-600 cells per 1 mm ² or 1 mL sample, about 1300-700 cells per 1 mm ² or 1 mL sample, about 1200-800 cells per 1 mm ² or 1 mL sample Cells: Approximately 1100 to 900 cells per 1 mm ² or 1 mL sample, or approximately 1050 to 950 cells per 1 mm ² or 1 mL sample. In one particular exemplary embodiment, a low CD8 + T cell density is about 10-1000 cells per 1 mm ² or 1 mL sample, about 20-900 cells per 1 mm ² or 1 mL sample, 1 mm ² or About 30-800 cells per 1 mL sample, about 40-700 cells per 1 mm ² or 1 mL sample, about 50-600 cells per 1 mm ² or 1 mL sample, about 50-600 cells per 1 mm ² or 1 mL sample 60-500 cells, about 70-400 cells per 1 mm ² or 1 mL sample, about 80-300 cells per 1 mm ² or 1 mL sample, or about 90-100 cells per 1 mm ² or 1 mL sample It is a cell of. In certain exemplary embodiments, the sample does not contain detectable CD8 + T cells.

Use of Oncolytic Virus in Neoadjuvant Therapy for Cancer The present invention provides a method for using an oncolytic virus for the treatment of cancer. For example, oncolytic viruses can be used in neoadjuvant therapy regimens for the treatment of cancer. Neoadjuvant therapy is generally given as a first step in shrinking the tumor prior to first-line treatment. Examples of first-line treatments include surgery, checkpoint inhibitor therapy (eg, anti-PD-1, anti-PD-L1, and anti-CTLA-4), BRAF inhibitor therapy, MEK inhibitor therapy, chemotherapy, and these. The combination can be mentioned. Examples of neo-adjuvant therapies include chemotherapy, radiation therapy, hormone therapy, checkpoint inhibitor therapy, BRAF inhibitor therapy, MEK inhibitor therapy, and oncolytic virus therapy. In certain embodiments, the first-line treatment is surgery and the neo-adjuvant therapy is an oncolytic virus.

In one embodiment, the invention relates to the treatment of cancer, wherein a neoadjuvant oncolytic virus is administered, followed by first-line treatment. In another embodiment, the invention relates to the treatment of cancer in which a neoadjuvant oncolytic virus is administered, followed by first-line treatment followed by adjuvant therapy. In another embodiment, the invention relates to the treatment of cancer in which a neoadjuvant oncolytic virus is administered in combination with checkpoint inhibitor therapy followed by first-line therapy followed by adjuvant therapy. In one embodiment, the neoadjuvant therapy is an oncolytic virus such as HSV-1 (eg, tarimogene laharparepbeck, RP1, RP2, or RP3). In one embodiment, neoadjuvant therapy includes oncolytic viruses such as HSV-1 (eg, tarimogene laharparepbeck, RP1, RP2, or RP3) and checkpoint inhibitors (eg, pembrolizumab, nivolumab, etc.). Anti-PD-1 or anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10). In another embodiment, neoadjuvant therapy includes oncolytic viruses such as HSV-1 (eg, tarimogene laharparepbeck, RP1, RP2, or RP3) and checkpoint inhibitors (eg, ipilimumab). It is a combination with anti-CTLA-4). In another embodiment, the first-line treatment is surgery. In yet another embodiment, the adjuvant therapy is a checkpoint inhibitor (eg, an anti-PD-1 antibody such as pembrolizumab, nivolumab, or an anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10). Is. In another embodiment, the oncolytic virus is tarimogene laharparepbeck.

Without being bound by logic, the present invention utilizes combination therapy to increase the rate of pCR (pathological complete response), RFS, and / or OS without undue toxicity. In addition, the neoadjuvant therapy regimen of the present invention can reduce or eliminate the amount and / or duration of first-line or adjuvant therapy for patients in treatment cost and treatment while maintaining clinical utility. The burden can be reduced.

Patients Untreated with Anti-PD-1 Therapy The present invention can be used to treat untreated patients prior to checkpoint inhibitor therapy (eg, anti-PD-1 such as pembrolizumab or nivolumab). That is, the patient has not previously received checkpoint inhibitor therapy.

In certain embodiments, the invention presents a neo-adjuvant tumor-soluble virus (eg, tarimogene laharparepbeck) with checkpoint inhibitor therapy (eg, pembrolizumab or any one of SEQ ID NOs: 1-10). Anti-PD-1 antibody, including one or more), followed by a first-line treatment (eg, surgery) followed by a checkpoint inhibitor (eg, pembrolizumab or any one of SEQ ID NOs: 1-10). Anti-PD-1 antibody) including the above. The present invention relates to the treatment of cancer by performing adjuvant therapy. In some embodiments, the cancer is melanoma, breast cancer (eg, triple negative breast cancer), kidney cancer, bladder cancer, colorectal cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, liver cancer, non-melanoma skin cancer, neuroendocrine A pediatric solid tumor with a tumor, T-cell lymphoma (eg, peripheral), or cancer of unknown primary origin, unresectable epidermal lesions. In some embodiments, the cancer is stage 3a, 3b, 3c, 3d, or 41a cancer. In certain embodiments, the cancer is melanoma (eg, stage 2 melanoma). In certain embodiments, the cancer is melanoma (eg, stage 3a, 3b, 3c, 3d, or 41a melanoma).

The appropriate dose can be determined, for example, by a doctor. In some embodiments, neoadjuvant therapy comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses. In certain embodiments, neoadjuvant therapy involves 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 oncolytic viruses (eg, tarimogene laharparepbeck, RP1, RP1, Includes administration of RP2, or RP3). In another embodiment, neoadjuvant therapy is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 checkpoint inhibitors (eg, pembrolizumab, nivolumab, or SEQ ID NOs: 1-10. Includes administration of an anti-PD-1 antibody) comprising any one or more of the above. In yet another embodiment, neoadjuvant therapy involves 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 oncolytic viruses (eg, tarimogene laharparepbeck, RP1). , RP2, or RP3) and 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 checkpoint inhibitors (eg, pembrolizumab, nivolumab, or SEQ ID NOs: 1-10). Includes a combination with administration of an anti-PD-1 antibody) comprising any one or more of them. In other embodiments, neoadjuvant therapy involves 1, 2, 3, 4, or 5 doses of oncolytic virus (eg, tarimogene laharparepbeck, RP1, RP2, or RP3) and 1 Includes combination with administration of two or three checkpoint inhibitors (eg, pembrolizumab, nivolumab, or an anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10). In still other embodiments, neoadjuvant therapy involves 1, 2, or 3 doses of oncolytic virus (eg, tarimogene laharparepbeck, RP1, RP2, or RP3) and 1, 2, ,. Alternatively, it comprises a combination of three checkpoint inhibitors (eg, pembrolizumab, nivolumab, or an anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10). In certain embodiments, neoadjuvant therapy comprises a combination of tarimogene laharparepbeck and pembrolizumab. In certain embodiments, neoadjuvant therapy comprises a combination of three doses of tarimogene laharparepbeck and a single dose of pembrolizumab or nivolumab.

In some embodiments, the first-line treatment involves surgery.

In some embodiments, adjuvant therapy is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 months checkpoint inhibitor therapy (eg,). , Anti-PD-1 such as pembrolizumab, nivolumab, or anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10). In other embodiments, adjuvant therapy is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-month checkpoint inhibitor therapy (eg, anti-antibodies such as pembrolizumab, nivolumab, etc.) PD-1, or an anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10). In some embodiments, adjuvant therapy is 3, 6, 9, or 12 months checkpoint inhibitor therapy (eg, anti-PD-1 such as pembrolizumab, nivolumab, or any of SEQ ID NOs: 1-10. Anti-PD-1 antibody) comprising one or more. In certain embodiments, adjuvant treatment comprises 6 or 12 months of treatment with pembrolizumab, nivolumab, or an anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10.

Patients for whom the aforementioned anti-PD-1 treatment was ineffective In yet another embodiment of the invention, the patient was ineffective prior to checkpoint inhibitor (eg, anti-PD-1 such as pembrolizumab or nivolumab) therapy. (Ie, it progressed after that). That is, the patient's disease progressed after receiving checkpoint inhibitor therapy.

In certain embodiments, the present invention administers a neoadjuvant oncolytic virus (eg, tarimogene laharparepbeck) in combination with checkpoint inhibitor therapy (eg, anti-CTLA-4 such as ipilimumab). The treatment of the cancer is followed by a first-line treatment (eg, surgery) followed by a checkpoint inhibitor (eg, anti-CTLA-4 such as ipilimumab) adjuvant therapy. In some embodiments, the cancer is melanoma, breast cancer (eg, triple negative breast cancer), kidney cancer, bladder cancer, colorectal cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, liver cancer, non-melanoma skin cancer, neuroendocrine A pediatric solid tumor with a tumor, T-cell lymphoma (eg, peripheral), or cancer of unknown primary origin, unresectable epidermal lesions. In some embodiments, the cancer is stage 3a, 3b, 3c, 3d, or 41a cancer. In certain embodiments, the cancer is melanoma (eg, stage 3a, 3b, 3c, 3d, or 41a melanoma).

The appropriate dose can be determined, for example, by a doctor. In some embodiments, neoadjuvant therapy comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses. In certain embodiments, neoadjuvant therapy involves 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 oncolytic viruses (eg, tarimogene laharparepbeck, RP1, RP1, Includes administration of RP2, or RP3). In another embodiment, neoadjuvant therapy involves administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 checkpoint inhibitors (eg, anti-CTLA-4 such as ipilimumab). including. In yet another embodiment, neoadjuvant therapy involves 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 oncolytic viruses (eg, tarimogene laharparepbeck, RP1). , RP2, or RP3) and 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 checkpoint inhibitors (eg, anti-CTLA-4 such as ipilimumab). Including combinations of. In other embodiments, neoadjuvant therapy involves 1, 2, 3, 4, or 5 doses of oncolytic virus (eg, tarimogene laharparepbeck, RP1, RP2, or RP3) and 1 Includes a combination with 2, 3, 4, or 5 doses of a checkpoint inhibitor (eg, anti-CTLA-4 such as ipilimumab). In still other embodiments, neoadjuvant therapy involves one, two, or three doses of oncolytic virus (eg, tarimogene laharparepbeck, RP1, RP2, or RP3) and 2, 3, 3. Alternatively, it comprises a combination with administration of four checkpoint inhibitors (eg, anti-CTLA-4 such as ipilimumab). In certain embodiments, neoadjuvant therapy comprises a combination of tarimogene laharparepbeck and ipilimumab. In certain embodiments, neoadjuvant therapy comprises a combination of three doses of tarimogene laharparepbeck and four doses of anti-CTLA-4 such as ipilimumab.

In some embodiments, the first-line treatment involves surgery.

In some embodiments, the adjuvant treatment is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. , 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 months checkpoint inhibitor therapy (eg, anti-CTLA-4 such as ipilimumab). In other embodiments, the adjuvant treatment is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20, Includes 21, 22, 23, or 24 months checkpoint inhibitor therapy (eg, anti-CTLA-4 such as ipilimumab). In some embodiments, adjuvant therapy comprises 3, 6, 9, 12, 15, 18, 21, or 24 months checkpoint inhibitor therapy (eg, anti-CTLA-4 such as ipilimumab). In certain embodiments, adjuvant treatment comprises treatment with ipilimumab for 12 or 24 months.

Early Stage Melanoma Patients In yet another embodiment of the invention, neoadjuvant therapy can be used to treat stage 1 or stage 2 cancer patients. In certain embodiments, the patient suffers from stage 1 or stage 2 melanoma. In another embodiment, the patient suffers from stage 1 melanoma. In another embodiment, the patient suffers from stage 2 melanoma.

In certain embodiments, the invention is administered with a neoadjuvant tumor-soluble virus (eg, tarimogene laharparepbeck) followed by first-line treatment (eg, surgery) followed by optional checks. Point inhibitors (eg, anti-CTLA-4 such as ipilimumab, or anti-PD-1 such as pembrolizumab, nivolumab, or anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10) adjuvant therapy. With respect to the treatment of stage 1 or stage 2 cancer (eg, melanoma) to be administered. In some embodiments, the cancer is stage 1 or stage 2 melanoma, breast cancer (eg, triple negative breast cancer), kidney cancer, bladder cancer, colorectal cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, liver cancer, non-black. Tumors Skin cancers, neuroendocrine tumors, T-cell lymphomas (eg, peripheral), or cancers of unknown primary origin, pediatric solid tumors with unresectable epidermal lesions. In certain embodiments, the cancer is stage 2 melanoma.

The appropriate dose can be determined, for example, by a doctor. In some embodiments, neoadjuvant therapy comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses. In certain embodiments, neoadjuvant therapy involves 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 oncolytic viruses (eg, tarimogene laharparepbeck, RP1, RP1, Includes administration of RP2, or RP3). In other embodiments, neoadjuvant therapy involves administration of 1, 2, 3, 4, 5, or 6 oncolytic viruses (eg, tarimogene laharparepbeck, RP1, RP2, or RP3). include. In yet another embodiment, neoadjuvant therapy comprises administration of 2, 3, 4, or 5 oncolytic viruses (eg, tarimogene laharparepbeck, RP1, RP2, or RP3). In certain embodiments, neoadjuvant therapy comprises tarimogene laharparepbeck. In certain embodiments, neoadjuvant therapy comprises four doses of Talimogene Laharparepbeck.

In some embodiments, the first-line treatment involves surgery.

In some embodiments, the optional adjuvant treatments are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, Includes 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 months checkpoint inhibitor therapy (eg, anti-CTLA-4 such as ipilimumab). In other embodiments, the optional adjuvant treatments are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, 21, 22, 23, or 24 months checkpoint inhibitor therapy (eg, anti-CTLA-4 such as ipilimumab). In some embodiments, the optional adjuvant therapy comprises 3, 6, 9, 12, 15, 18, 21, or 24 months checkpoint inhibitor therapy (eg, anti-CTLA-4 such as ipilimumab). .. In certain embodiments, the optional adjuvant treatment comprises treatment with ipilimumab for 12 or 24 months.

In some embodiments, the optional adjuvant treatment is a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15-month checkpoint inhibitor. Therapies include anti-PD-1 such as pembrolizumab, nivolumab, or anti-PD-1 antibodies comprising any one or more of SEQ ID NOs: 1-10. In other embodiments, the optional adjuvant therapy is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months checkpoint inhibitor therapy (eg, pembrolizumab, nivolumab). Anti-PD-1 such as, or anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10). In some embodiments, the optional adjuvant therapy is of 3, 6, 9, or 12 months checkpoint inhibitor therapy (eg, anti-PD-1 such as pembrolizumab, nivolumab, or SEQ ID NOs: 1-10. Anti-PD-1 antibody) comprising any one or more of the above. In certain embodiments, the optional adjuvant treatment comprises 6 or 12 months of treatment with pembrolizumab, nivolumab, or an anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10.

Patients with low CD8 + cell density at baseline The present invention can be used to treat patients with low CD8 + cell density at baseline. It has been observed that treatment with Tarimogene Laharparepbeck resulted in an increase in CD8 + cell density within the tumor (see Figure 8). Importantly, this increase in CD8 + cell density in the tumor after treatment with Talimogene Laharparepbeck correlates with longer RFS (sensitivity analysis) and longer OS (see Figure 9). I want to be). Therefore, in some embodiments, the treatment regimen of the invention is used to treat patients with "cold" tumors, i.e., tumors with low levels of CD8 + cell density within the tumor at baseline. In particular, administration of a neoadjuvant oncolytic virus (eg, Tarimogene Laharparepbeck) to a "cold" tumor can result in subsequent first-line (eg, surgery) outcomes (eg, RFS and OS). improves.

In certain embodiments, patients with "cold" tumors are selected for treatment according to the treatment regimen of the present invention. In certain embodiments, the patient has about 3000 or less per sample with a CD8 + T cell density of 1 mm ² or 1 mL (ie 1 cm ³ ), eg, about 3000, about 2900, about 2800, about 2700, about 2600. , About 2500, about 2400, about 2300, about 2200, about 2100, about 2000, about 1900, about 1800, about 1700, about 1600, about 1500, about 1400, about It suffers from cold tumors of 1300, about 1200, about 1100, about 1000, about 900, about 800, about 700, about 600, or less than about 500 cells. In some embodiments, the patient has a CD8 + T cell density of about 1500, about 1400, about 1300, about 1200, about 1100, about 1000, about 900, about 800, about 700, about 600, or about 500 cells / mm. I have a cold tumor of ² or less.

Oncolytic virus In one embodiment, the oncolytic virus used in the present invention is an adenovirus, leovirus, measles virus, herpes simplex virus, Newcastle disease virus, Seneca virus, or vaccinia virus. In certain embodiments, the oncolytic virus is herpes simplex virus (HSV). In an exemplary embodiment, the oncolytic virus is derived from a herpes simplex virus type 1 (HSV-1) or herpes simplex type 2 (HSV-2) strain or a derivative thereof, preferably HSV-1. Examples of the inducing strain include heterologous recombinant strains containing DNA derived from HSV-1 and HSV-2 strains. Such heterologous recombinant strains are described in the art, for example, from Thompson et al. , (1998) Virus Genes 1 (3); 275286 and Meignier et al. , (1998) J.M. Infect. Dis. 159; 602614.

The herpes simplex virus strain may be derived from a clinical isolate. Such strains are isolated from infected individuals who are likely to suffer from recurrent herpes simplex. As described in US Pat. Nos. 7,063,835 and 7,223,593, clinical isolates are in vitro and / or in vivo compared to standard laboratory strains. Can be screened for the desired ability or characteristics, such as enhanced replication in tumors and / or other cells, each of which is incorporated by reference in its entirety. In one embodiment, the herpes simplex virus is a clinical isolate derived from recurrent herpes simplex. Further examples of herpes simplex virus type 1 virus strains include, but are not limited to, JS1 strain, 17+ strain, F strain, KOS strain and Patton strain.

Examples of HSV genes that can be modified include pathogenic genes encoding proteins such as ICP34.5 (γ34.5). ICP34.5 acts as a virulence factor during HSV infection, limiting replication in non-dividing cells and making the virus non-pathogenic. Another HSV gene that can be modified is the gene encoding ICP47. ICP47 downregulates the expression of major histocompatibility complex (MHC) class I on the surface of infected host cells and the binding of MHC class I to antigen presentation-related transporters (TAPs). Such action blocks the transport of antigenic peptides and the loading of MHC class I molecules in the endoplasmic reticulum. Another HSV gene that can be modified is ICP6, a large subunit of ribonucleotide reductase that is involved in nucleotide metabolism and viral DNA synthesis in non-dividing cells but not in dividing cells. .. Thymidine kinase (involved in phosphorylating acyclovir to acyclovir monophosphate), virion trans-activating protein vmw65, glycoprotein H, vhs, ICP43, and the most encoding ICP4, ICP27, ICP22 and / or ICP0 Early genes can also be modified (in addition to or in place of the genes listed above).

The herpesvirus strain and the method for producing such a strain are described in US Pat. No. 5,824,318; 6,746,675; 6,770,274; , 063,835; 7,223,593; 7,749,745; 7,744,899; 8,273,568. No. 8,420,071; and 8,470,577; International Publication No. 199600007; 199639841; 2006002394 pamphlet; and 2013306795 pamphlet; CN 128303, CN 10230334 and CN10230335; Virology and Rabkin, (2002) Cancer Gene Therapy 9: 967-97 and Cassady and. It is also described in Ness Parker, (2010) The Open Virology Journal 4: 103-108, which is incorporated by reference in its entirety.

In one embodiment, the oncolytic virus is a clinical strain (HSV-1 strain JS1) derived from a clinical strain (HSV-1 strain JS1) deposited with European trademark of cell cultures (ECAAC) as accession number 01010209. (Registered trademark)). The HSV-1 viral gene encoding ICP34.5 and ICP47 is functionally deleted in Tarimogene Laharparepbeck. Functional deletion of ICP47 results in early expression of US11, a gene that promotes viral growth in tumor cells without reducing tumor selectivity. The coding sequence for human GM-CSF has been inserted into the viral genome at the site of the former ICP34.5 (see Liu et al., Gene Ther 10: 292-303, 2003).

In some embodiments, the tumor lytic virus lacks the gene encoding functional ICP34.5, lacks the gene encoding functional ICP47, and comprises a nucleic acid encoding the Fms-associated tyrosine kinase 3 ligand (FLT3L). , HSV-1 containing nucleic acid encoding interleukin-12 (IL-12). In some embodiments, the oncolytic virus is derived from a clinical strain (HSV-1 strain JS1) deposited with European culture of cell cultures (ECAAC) as accession number 01010209.

Other examples of oncolytic viruses include RP1 (HSV ^- 1 / ICP34.5- / ICP47- / GM-CSF / GALV ^- GP R ( ^- ); RP2 (HSV ^- 1 / ICP34.5- / ICP47-). / GM-CSF / GALV-GP R (-) / anti-CTLA-4 binder; and RP3 (HSV ^- 1 / ICP34.5- / ICP47- / GM-CSF / GALV ^- GP R (-) / anti-CTLA- 4 Binding agents / costimulatory ligands (eg, CD40L, 4-1BBL, GITRL, OX40L, ICOSL). In such oncolytic viruses, GALV (tenagazal leukemia virus) is a specific deficiency of R-peptide. It has been modified by loss, which gives GALV-GP R (-). Such oncolytic viruses are described in International Publication No. 2017118864, No. 2017118865, No. 2017118866, No. Discussed in 2017118867 and 2018127713A1 pamphlets, each of which is incorporated by reference in its entirety.

Further examples of oncolytic viruses include NSC-733972, HF-10, BV-2711, JX-594, Myb34.5, AE-618, Brainwel ™ and Heapwel ™, Cavatak® (registered trademark). Coxsackievirus, CVA21), HF-10, Seprehvir®, Pelareorep®, endenotucilev, ONCR-177 and US Pat. No. 10,105,404, International Publication No. 10. Examples include those described in the 20086005 pamphlet, the 2018026872A1 pamphlet and the 2017181420 pamphlet, each of which is incorporated by reference in its entirety.

Further examples of oncolytic viruses include:

[A] G207, a tumor-soluble HSV-1 derived from the F strain of wild-type HSV-1, a major determinant of HSV neurotoxicity, deletions in both copies of the ICP34.5 gene, and infected cellular protein 6 It has an inactivated insertion of the lacZ gene of E. coli in UL39 encoding (ICP6) (see Mineta et al. (1995) Nat Med. 1: 938-943).

[B] Herpes simplex virus with deletion of both copies of OrienX010, i.e. γ34.5 and ICP47 gene, interruption of ICP6 gene, and insertion of human GM-CSF gene (Liu et al., (2013) World Journal of Gastrology). 19 (31): 5138-5143).

[C] A herpes simplex virus in which the junction region of the long (L) and short (S) regions is deleted, which comprises one copy of NV1020, ICP34.5, UL24 and UL56.34,35. Deleted regions were replaced with HSV-2 US DNA (US2, US3 (PK), gJ and gG) fragments (Todo, et al. (2001) Proc Natl Acad Sci USA. 98: 6396-6401). I want to be).

[D] M032, a herpes simplex virus with a deletion of both copies of the ICP34.5 gene and insertion of interleukin 12 (see Cassday and Ness Parker, (2010) The Open Virology Journal 4: 103-108). ..

[E] ImmunoVEX HSV2, a herpes simplex virus (HSV-2) with a functional deletion in the genes encoding vhs, ICP47, ICP34.5, UL43 and US5.

[F] OncoVEX ^{GALV / CD} is also derived from the JS1 strain of HSV-1, and the genes encoding ICP34.5 and ICP47 are functionally deleted, and instead of this ICP34.5 gene, cytosine deaminase and A gene encoding the tenagazal leukemia fusion glycoprotein has been inserted into the viral genome.

The herpes simplex virus of the present invention may also contain one or more heterologous genes. Heterologous genes are genes that are introduced into the genome of a virus and are homologues of genes that are not normally found in the genome of the virus or are expressed in viruses of different species and have different nucleic acid sequences. , Refers to those that act through different biochemical mechanisms. Heterologous genes are one or more proteins, such as cytotoxicities, immunomodulatory proteins (ie, proteins that enhance or suppress the host immune response to the antigen), tumor antigens, prodrug activators, tumor suppressors, prodrug conversions. It may encode an enzyme, a protein capable of causing cell-cell fusion, a TAP inhibitor, an antisense RNA molecule, or a ribozyme. Examples of immunomodulatory proteins include, for example, cytokines. Examples of cytokines include interleukins such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-. 11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-20; interferon α, interferon β or interferon γ, tumor necrosis factor alpha (TNFα) , CD40L, granulocyte macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF) and granulocyte colony stimulating factor (G-CSF), chemokine (neutrophil activating protein (NAP), macrophage run Chemical activator (MCAF), RANTES and macrophage inflammatory peptides MIP-1a and MIP-1b, etc.), complement components and their receptors, immune system accessory molecules (eg, B7.1 and B7.2),. Adhesive molecules (eg, ICAM-1, 2 and 3) and adhesion acceptor molecules can be mentioned. Tumor antigens include E6 and E7 antigens of human papillomavirus, EBV-derived proteins, mucins such as MUC1, melanoma tyrosinase, and MZ2-E. Examples of the prodrug activator include nitroreductase and cytochrome p450, examples of the tumor suppressor include p53, and examples of the prodrug converting enzyme include cytosine deaminase. Examples of proteins that can induce cell-cell fusion include gibbon leukemia fusion glycoprotein. TAP inhibitors include bovine herpesvirus (BHV) UL49.5 polypeptide. Antisense RNA molecules can be used to block the expression of cellular or pathogen mRNA. The RNA molecule can be a ribozyme (eg, hammerhead or hairpin ribozyme) designed to repair RNA in deficient cells or destroy RNA encoded by unwanted cells or pathogens. ..

It also includes the insertion of multiple viral genes into the herpes simplex genome, such as the insertion of one or more copies of the gene encoding the viral protein Us11.

Tarimogene Laharparepbeck, HSV-1 [JS1 strain] ICP34.5- / ICP47- / hGM-CSF (conventionally known as OncoVex ^GM-CSF ) replicates selectively within solid tumors. Oncolytic immunotherapy delivered intratumorally, including immunopotentiating HSV-1 (Lui et al., Gene Therapy, 10: 292-303, 2003; US Pat. No. 7,223,593 and US Pat. No. 7,537,924). HSV-1 was derived from the JS1 strain deposited with European collection of cell cultures (ECAAC) under accession number 01010209. The HSV-1 viral gene encoding ICP34.5 is functionally deleted in Tarimogene Laharparepbeck. A functional deletion of ICP34.5, which acts as a virulence factor during HSV infection, limits replication in non-dividing cells and makes the virus non-pathogenic. The safety of HSV functionally deficient in ICP34.5 has been shown in multiple clinical trials (MacKie et al, Ranchet 357: 525-526, 2001; Markert et al, Gene Ther 7: 867- 874,2000; Lampling et al, Gene Ther 7: 859-866, 2000; Sundaresan et al, J. Virol 74: 3822-3841,2000; Hunter et al, J Virol Aug; 73 (8): 6319-6326, 1999). In addition, ICP47, which blocks the presentation of viral antigens to major histocompatibility complex class I and II molecules, has been functionally deleted from Talimogene Laharparepbeck. Functional deletion of ICP47 also results in early expression of US11, a gene that promotes viral growth in tumor cells, without reducing tumor selectivity. The viral genome of Tarimogene Laharparepbeck has a coding sequence for human GM-CSF, a cytokine involved in stimulating an immune response. Replacing almost all of the ICP34.5 gene by inserting the gene encoding the human GM-CSF nullifies any potential recombination event between the tarimogene Laharparepbeck and the wild-type virus. It is possible to reliably bring about only the non-pathogenic virus, and it is impossible to bring about the production of wild-type virus that carries the gene for human GM-CSF. The HSV thymidine kinase (TK) gene remains intact in the tarimogene laharparepbeck, which makes the virus susceptible to antiviral agents such as acyclovir. Therefore, acyclovir may be used as needed to inhibit replication of tarimogene laharparepbeck.

Tarimogene Laharparepbeck results in a direct oncolytic effect by viral replication in the tumor and induction of an antitumor immune response enhanced by local expression of GM-CSF. Since melanoma is a disseminated disease, this dual activity is beneficial as a therapeutic treatment. The intended clinical effects include destruction of the injected tumor, destruction of localized local and distant non-injected tumors, reduction of the formation of new metastases, and overall post-treatment of the first existing disease. The rate of progression and the rate of recurrence are reduced, and the overall survival time is extended.

Tarimogene Laharparepbeck has been tested for efficacy in various in vitro (cell lines) and in vivo murine tumor models and eradicates or tumors at doses comparable to those used in clinical trials. It has been shown to substantially inhibit the growth of mice. Also, by nonclinical evaluation, GM-CSF enhanced the resulting immune response, enhancing both the response of injected tumors and the response of non-injected tumors, and increased MHC class I molecules. It has been confirmed that surface levels result from the deletion of ICP47. Tarimogene Laharparepbeck has been injected into normal mice and cancer-bearing mice, and its safety has been evaluated. The virus was generally well tolerated and showed no signs of safety concern at doses of up to 1 × 10 ⁸ PFU per dose (eg, Liu et al., Gene Ther 10: 292-303). , 2003).

Clinical trials of several advanced tumor types (advanced solid tumors, melanoma, squamous cell carcinoma of the head and neck, and pancreatic cancer) in more than 400 subjects treated with Talimogene Laharparepbeck Has been or is being performed (eg, Hu et al., Clin Can Res 12: 6737-6747, 2006; Harlington et al., J Clin Oncol. 27 (15a): abstract 6018, 2009; Kaufman et al. , Ann Surgic Oncol. 17: 718-730, 2010; see Kaufman and Bines, Future Oncol. 6 (6): 941-949, 2010). Clinical data indicate that Tarimogene Laharparepbeck may provide overall clinical utility in patients with advanced melanoma. A high rate of complete response was achieved, especially in stage 3c to stage 4 melanoma (Scener et al., J. Clin. Oncol. 271 (12): 907-913, 2009). In addition, response was observed at both the injected and non-injected sites, including the visceral site.

Tarimogene Laharparepbeck is available for injectable skin, subcutaneous and lymph node tumors at doses of up to 4.0 mL of ¹⁰⁶ plaqueforming units / mL (PFU / mL) on day 1 of week 1. Then, on the first day of the 4th week, a dose of ¹⁰⁸ PFU / mL up to 4.0 mL is administered by intratumoral infusion every 2 weeks (± 3 days) thereafter. The recommended amount of Talimogene Laharparepbeck to be injected into the tumor depends on the size of the tumor and should be determined according to the injection volume guidelines in Table 1.

All reasonably injectable lesions (skin, subcutaneous and lymph node disorders that can be injected with or without ultrasound guidance) should be infused at the maximum dose effective for each individual case. For each treatment day, it is recommended to prioritize injections as follows: new injectable tumors that have emerged since the last injection; by tumor size, starting with the largest tumor; previous injections Any tumor that could not be injected, but is now injectable.

The duration of therapy is continued as long as there is medical instruction or until the desired therapeutic effect (eg, as described herein) is achieved. For example, Response Evolution Criteria in Solid Tumors (RECIST) may be used to treat patients with Talimogene Laharparepbeck until complete response, elimination of all injectable tumors, or disease progression. can. Due to the mechanism of action, patients may experience the growth of existing tumors or the emergence of new tumors before the clinical usefulness of Talimogene Laharparepbeck is maximized. Therefore, at least 6 months from the first dose, provided that the subject has no evidence of clinically significant deterioration of health that requires discontinuation of treatment and is tolerable to treatment. It is expected that interim administration should be continued. However, the course of treatment for any individual patient can be modified in clinical practice.

First-line treatment Any first-line treatment within the treatment regimen of the invention described herein includes surgery, checkpoint inhibitor therapy (eg, anti-PD-1, anti-PD-L1, and anti-CTLA-4). BRAF inhibitor therapy, MEK inhibitor therapy, or a combination thereof may be used. In certain embodiments, the first-line treatment is surgery.

Adjuvant Therapy Any adjuvant therapy in the treatment regimen of the invention described herein is checkpoint inhibitor therapy (eg, anti-PD-1, anti-PD-L1, and anti-CTLA-4), BRAF inhibition. It may be drug therapy, MEK inhibitor therapy, or a combination thereof. In certain embodiments, the adjuvant therapy is a checkpoint inhibitor (eg, anti-CTLA-4 such as ipilimumab; or anti-PD-1 such as pembrolizumab, nivolumab, or any one or more of SEQ ID NOs: 1-10. Anti-PD-1 antibody).

The immune system has multiple inhibition pathways that are essential for maintaining autoimmune tolerance and regulating the immune response. In T cells, the swing and properties of their response are elicited via antigen recognition by the T cell receptor and regulated by immune checkpoint proteins that balance co-stimulation and inhibitory signals.

Cell-damaging T lymphocyte-related protein 4 (CTLA-4) is an immune checkpoint molecule that down-regulates the pathway of T cell activation (Fong et al., Cancer Res. 69 (2): 609-615, 2009; Weber Cancer Immunol. Immunother, 58: 823-830, 2009). Blocking CTLA-4 has been shown to enhance T cell activation and its proliferation. Examples of CTLA-4 inhibitors include anti-CTLA-4 antibodies. The anti-CTLA-4 antibody binds to CTLA-4 and blocks CTLA-4's interaction with its ligand CD80 / CD86 expressed on antigen-presenting cells. This blocks the negative downregulation of the immune response evoked by the interaction of these molecules. Examples of anti-CTLA-4 antibodies are US Pat. Nos. 5,811,097; 5,811,097; 5,855,887; 6,051,227. No. 6,207,157; 6,682,736; 6,984,720; and 7,605,238. Has been done. Anti-CDLA-4 antibodies include tremelimumab (thicilimumab, CP-675,206). In one embodiment, the anti-CTLA-4 antibody is ipilimumab (10D1, also known as MDX-D010), a fully human monoclonal IgG antibody that binds to CTLA-4. Ipilimumab is marketed under the name Yervoy® and is approved for the treatment of unresectable melanoma or metastatic melanoma.

Another immune checkpoint protein is Programmed Cell Death 1 (PD-1). PD-1 is either by specific antigen target or during mixed lymphocyte reaction by limiting the activity of T cells in peripheral tissues during the inflammatory response to infection and by limiting autoimmune PD-1 blockade in vitro. T cell proliferation and cytokine production are enhanced in response to allogeneic cell challenges. A strong correlation between PD-1 expression and response was shown by blocking PD-1 (Pardall, Nature Reviews Cancer, 12: 252-264, 2012). Blocking of PD-1 can be achieved by various mechanisms including antibodies that bind to PD-1 or its ligand PD-L1. Examples of PD-1 and PD-L1 blocking agents are US Pat. Nos. 7,488,802, 7,943,743; 8,008,449; 8,8, Specification 168,757; Specification 8,217,149, PCT International Publication No. 03042402 Pamphlet, International Publication No. 2008156712 Pamphlet, International Publication No. 200889411 Pamphlet, International Publication No. 2010036959 Pamphlet, International Publication It is described in Pamphlet 2011066342, Pamphlet International Publication No. 2011159877, Pamphlet International Publication No. 2011082400, and Pamphlet International Publication No. 2011116699. In certain embodiments, the PD-1 blocker comprises an anti-PD-L1 antibody. In certain other embodiments, the PD-1 blocker is an anti-PD-1 antibody and a similar binding protein such as nivolumab (MDX 1106, BMS 936558, ONO 4538), which binds to PD-1 and its ligand. Completely human IgG4 antibody that blocks PD-1 activation by PD-L1 and PD-L2; pembrolizumab (MK-3475 or SCH 900475), humanized monoclonal IgG4 antibody against PD-1; humanization that binds to PD-1 Antibody, CT-011; AMP-224, a fusion protein of B7-DC; antibody Fc portion; BMS-936559 (MDX-1105-01), which blocks PD-L1 (B7-H1); PD-1 antibody).

In certain embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) is one of SEQ ID NOs: 1-6 (representing HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 in that order). Includes one, two, three, four, five or all six CDR amino acid sequences. In certain embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises all six of the CDR amino acid sequences of SEQ ID NOs: 1-6. In other embodiments, the anti-PD-1 antibody (or its antigen-binding antibody fragment) is (a) sequence number 7 or a variant sequence thereof (only one or two amino acids differing or at least or about 70% of the sequence. Heavy chain variable region amino acid sequence (having homology), or (b) light of SEQ ID NO: 8 or a variant sequence thereof (only one or two amino acids differ or have at least or about 70% sequence homology). Includes a chain variable region amino acid sequence. In an exemplary embodiment, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 7 and the light chain variable region amino acid sequence of SEQ ID NO: 8. In other embodiments, the anti-PD-1 antibody (or its antigen-binding antibody fragment) is (a) sequence number 9 or a variant sequence thereof (only one or two amino acids differing or at least or about 70% of the sequence. Heavy chain amino acid sequence (having homology); or (b) Light chain amino acid of SEQ ID NO: 10 or its variant sequence (only one or two amino acids differ or have at least or about 70% sequence homology). Contains sequences. In an exemplary embodiment, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10.

In certain embodiments, the anti-PD-1 antibody is encoded by one or more nucleic acid sequences (or antigen-binding portions thereof). In an exemplary embodiment, the antibody is one, two, of the CDRs encoded by the nucleic acids of SEQ ID NOs: 11-16 (in turn representing HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3). Includes 3, 4, 5, or all six. In another exemplary embodiment, the antibody comprises all six of the CDRs encoded by the nucleic acids of SEQ ID NOs: 11-16. In some embodiments, the anti-PD-1 antibody (or antigen-binding portion thereof) is (a) nucleic acid of SEQ ID NO: 17 or a variant thereof (1, 2, 3, 4, 5, 5 or 6 nucleic acids). Heavy chain variable regions that differ only or have at least or about 70%, 85%, 90% or 95% sequence homology), or (b) SEQ ID NO: 18 or a variant sequence thereof (one, Only two, three, four, five or six nucleic acids differ or have at least or about 70%, 85%, 90% or 95% sequence homology) of the light chain variable region. include. In an exemplary embodiment, the anti-PD-1 antibody (or antigen-binding portion thereof) comprises a heavy chain variable region encoded by SEQ ID NO: 17 and a light chain variable region encoded by SEQ ID NO: 18. In other embodiments, the anti-PD-1 antibody (or antigen-binding portion thereof) is (a) only nucleic acids of SEQ ID NO: 19 or a variant sequence thereof (1, 2, 3, 4, 5, or 6 nucleic acids). Is different or at least or has about 70%, 85%, 90% or 95% sequence homology), or (b) SEQ ID NO: 20 or a variant sequence thereof (one, two, Only 3, 4, 5 or 6 nucleic acids differ or include at least or about 70%, 85%, 90% or 95% sequence homology) encoded by the light chain. In an exemplary embodiment, the anti-PD-1 antibody (or antigen-binding portion thereof) comprises a heavy chain encoded by SEQ ID NO: 19 and a light chain encoded by SEQ ID NO: 20.

Other immune checkpoint inhibitors include lymphocyte activation gene-3 (LAG-3) inhibitors such as IMP321, soluble Ig fusion protein (Brignone et al., 2007, J. Immunol. 179: 4202-4211). Can be mentioned. Other immune checkpoint inhibitors include B7 inhibitors such as B7-H3 and B7-H4 inhibitors. In particular, an anti-B7-H3 antibody, MGA271 (Loo et al., 2012, Clin. Cancer Res. July 15 (18) 3834) can be mentioned. In addition, TIM3 (T cell immunoglobulin domain and mucin domain 3) inhibitors (Fourcade et al., 2010, J. Exp. Med. 207: 2175-86 and Sakuishi et al., 2010, J. Exp. Med. 207). : 2187-94) is also mentioned.

Kits Kits for use by physicians include the oncolytic viruses of the invention (eg, simple herpesvirus type 1, lacking the functional ICP34.5 gene, lacking the functional ICP47 gene, and human GM-CSF. Using simple herpesviruses containing the encoding gene, such as Talimogene Laharparepbeck, and oncolytic viruses as neoadjuvant therapy, melanoma, breast cancer (eg, triple negative breast cancer), kidney cancer, bladder cancer. , Colon-rectal cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, liver cancer, non-black tumor skin cancer, neuroendocrine tumor, T-cell lymphoma (eg peripheral), or cancer of unknown primary origin, treating pediatric solid tumors with unresectable epidermal lesions Includes attachments and labels with instructions to do so. In some embodiments, the cancer is stage 3a, 3b, 3c, 3d, or 41a cancer. In certain embodiments, the cancer is melanoma (eg, stage 2 melanoma). In certain embodiments, the cancer is melanoma (eg, stage 3a, 3b, 3c, 3d, or 41a melanoma). In certain embodiments, the oncolytic virus is tarimogene laharparepbeck, RP1, RP2, or RP3. In another embodiment, the oncolytic virus is tarimogene laharparepbeck.

In another embodiment, the invention is a herpes simplex virus comprising [1] a functional ICP34.5 gene, a functional ICP47 gene, and a gene encoding human GM-CSF, and [2] oncolytic virus. Instructions are given to treat the cancer by administering the sex virus in combination with the first checkpoint inhibitor, surgically removing any residual tumor, and administering the second checkpoint inhibitor. With respect to a kit comprising an attachment or label, wherein the first and second checkpoint inhibitors may be the same or different. In some embodiments, the oncolytic virus is tarimogene laharparepbeck, RP1, RP2, or RP3. In another embodiment, the oncolytic virus is tarimogene laharparepbeck. In some embodiments, the first and second checkpoint inhibitors may be selected independently from the list containing CTLA-4 blockers, PD-1 blockers, and PD-L1 blockers. In some embodiments, the CTLA-4 blocker is an anti-CTLA-4 antibody, the PD-1 blocker is an anti-PD-1 antibody, and the PD-L1 blocker is an anti-PD-L1 antibody. The CTLA-4 blocker may be ipilimumab. The PD-1 blocker may be nivolumab, pembrolizumab, CT-011, AMP-224, semiprimab, or an anti-PD-1 antibody comprising any one or more of SEQ ID NOs: 1-10. The PD-L1 blocker may be atezolizumab, avelumab, durvalumab, or BMS-936559.

In another embodiment, the invention relates to a method of making such a kit.

Unless otherwise defined herein, scientific and technical terms used in the context of the present invention shall have meaning generally understood by one of ordinary skill in the art. Further, unless contextually requires a different interpretation, the singular term shall include the plural and the plural term shall include the singular. Generally, naming schemes and techniques used in connection with cell and tissue culture, molecular biology, immunology, microbiology, genetics, and the chemistry and hybridization of proteins and nucleic acids described herein are in the art. It is well known and commonly used in. Unless otherwise indicated, the methods and methods of the invention are generally practiced according to conventional methods well known in the art and such methods and methods are various general that are cited and discussed throughout this specification. It is described in references and highly specific references. All identified patents and other publications are expressly incorporated herein by reference in their entirety.

The following examples are provided to illustrate a particular embodiment or feature of the invention and are not intended to limit its scope.

Example 1: The efficacy and safety of Talimogene Laharparepbeck's neo-adjuvant treatment combined with surgery for resectable stage 3B to 4M1a melanoma was evaluated in comparison with surgery alone. Two-phase multicenter randomized open-label clinical trial Resectable stage 3B / C / 4M1a MEL ≧ 1, injectable skin lesions, subcutaneous lesions, or lymph node lesions ≧ 10 mm, and previously undergoing systemic treatment for 3 months Patients who did not have a 1: 1 ratio were randomized, and after 6 doses of Talimogene Laharparepbeck every 12 weeks, surgery was performed between 13 and 18 weeks (arm 1), and the study was performed against it. Surgery was performed in advance during the 1st to 6th weeks of the procedure (arm 2). Please refer to the chart in FIG. Tarimogene Laharparepbeck was administered at standard doses until surgery until no tumor was injectable or intolerant. A set of ITTs was analyzed and evaluated as having a one-year RFS difference between the groups. RFS events were defined as local, regional, or distant recurrence of melanoma, the first recurrence, or death resulting from any postoperative case. Patients who were not confirmed to be disease-free after surgery (ie, the surgical result was not R0) or who withdrew before surgery were considered events at the time of RFS randomization. Sensitivity analysis did not take into account the surgical outcome of R0 and calculated the RFS from randomization to the day of the removal event.

150 patients were randomized (76 on arm 1 and 74 on arm 2). As planned, 75% of arm 1 and 93% of arm 2 were operated on. The ratio of R0 was 37.8% (arm 2) with respect to 42.1% (arm 1). The ratio of R1 (arm 2 to arm 1, respectively) was 31.6% with respect to 51.4%. The ratio of R2 was 1.3% with respect to 4.1%. At 1 year, 33.5% of patients with Arm 1 and 21.9% of patients with Arm 2 remained relapse-free. (HR 0.73, P = 0.048). The percentage of OS at 1 year was 95.9% for arm 1 patients and 85.8% for arm 2 patients (HR 0.47, P = 0.078). Sensitivity analysis showed that 55.8% of patients with Arm 1 and 39.3% of Arm 2 remained relapse-free at the 1-year landmark (HR 00.63, P = 0.0024). ).

Neoadjuvant Talimogene Laharparepbeck demonstrated improved recurrence-free survival at 1 year compared to surgery alone, 39.3% vs. 53.8% and HR 00, respectively. It was .63, P = 0.0024. 95.9% of patients with arm 1 and 85.8% of patients with arm 2 survived after 1 year (HR 0.47, P = 0.078). Overall survival for 2 years was 88.9% for arm 1 and 77.4% for arm 2 (HR: 0.49, P = 0.050).

These results show that [1] in resectable stage IIIB-IVM1a melanoma, the neoadjuvant Talimogene Laharparepbeck improved 2-year RFS and OS, and [2] neoadjuvant oncolytic virus. It has been shown that it is possible to reduce the amount and / or duration of adjuvant therapy, for example, by using viral therapy (eg, tarimogene laharparepbeck).

In addition, in arm 1, treatment with Talimogene Laharparepbeck triples the number of CD8 + cells in the tumor (P <0.001) and increases PD-L1 (P ≦ 0.05). ). Both the mean CD8 ⁺ density of arm 1 and the mean H score of PD-L1 after treatment were significantly higher than the mean of arm 2 (P <0.001 in both comparisons; see FIG. 8). thing). The improved intratumoral CD8 + density after treatment correlated with longer RFS and OS (see Figure 9). These results indicate that post-treatment T cell influx and upregulation of PD-L1 after treatment with Tarimogene Laharparepbeck assists the role of the adaptive immune system.
Purpose Main purpose:
-Relapse-free survival (RFS) is estimated by comparing the therapeutic effect of the neoadjuvant Tarimogene Laharparepbeck with surgery to the therapeutic effect of surgery alone.
Secondary purpose:
• Estimate 1-year, 2-year, 3-year, and 5-year RFS by comparing the effect of the neoadjuvant Talimogene Laharparepbeck with surgery to the effect of surgery alone.
Estimate the rate of surgical resection of the histopathological tumor-free margin (R0) by comparing the effect of the neoadjuvant Talimogene Laharparepbeck with surgery to the effect of surgery alone. ..
The effect of the neoadjuvant Talimogene Laharparepbeck is estimated for the rate of complete pathological response (pCR).
The effects of the neoadjuvant Tarimogene Laharparepbeck in combination with surgery were compared to the effects of surgery alone, with local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free. Estimate survival (DMFS).
Estimate 1-year, 2-year, 3-year, 5-year, and overall survival (OS) by comparing the effects of the neoadjuvant Talimogene Laharparepbeck with surgery to the effects of surgery alone. ..
The response of the neoadjuvant Talimogene Laharparepbeck is estimated globally and individually for lesions injected during treatment and those not injected (arm 1 only).
-Evaluate the safety of the neoadjuvant Tarimogene Laharparepbeck with surgery compared to the safety of surgery alone.
result:

Example 2: Anti-PD- Phase 3 Placebo Randomized Multicenter Clinical Trials Designed to Evaluate Efficacy and Safety in One Therapy Approximately 700 Eligible Subjects in 1: 1 on the Treatment Arms: Randomized by ratio.
Arm A: Subject who received Talimogene Laharparepbeck + PD-1 inhibitor in neoadjuvant setting before excision Arm B: Subject who received placebo + PD-1 inhibitor in neoadjuvant setting before excision

Arm A subjects with 3 doses of Talimogene Laharparepbeck (1st week: ¹⁰⁶ PFU / mL up to 4mL, 4th, 7th week) using treatment regimens known in the art. Eyes: Received administration of ¹⁰⁸ PFU / mL (up to 4 mL) and anti-PD-1 therapy. Subjects in Arm B received placebo and anti-PD-1 therapy at weeks 1, 4, and 7 in a neoadjuvant setting.

All subjects underwent resection at week 10 and subsequently received anti-PD-1 therapy with an adjuvant setting for 1 year. Subjects undergo radiographic evaluation prior to resection and tumor response is assessed every 3 months after resection, which is assessed by an independent reader. The primary endpoint is event-free survival (EFS), and the primary secondary endpoints are overall survival (OS), disease-free survival (DFS), complete pathological response (pCR), and tumor response (RECIST). 1.1) Evaluation items (response rate (ORR), complete response (CR), partial response (PR), stable disease (SD), disease progression (PD)). In this clinical trial, subjects were followed up for 5 years.

In this study, the stage of the disease may be extended to include stage 2 resectable melanoma. In addition, postoperative pCR may be used to guide adjuvant therapy to one arm of the study.

The duration of the adjuvant anti-PD-1 treatment may be adjusted to less than one year.

In addition, both OS and EFS / DFS co-primary endpoints may be evaluated.

Claims (36)

It ’s a cancer treatment method.
The combination of an oncolytic virus and a first checkpoint inhibitor, and
Surgical removal of any residual tumor and
Administering a second checkpoint inhibitor and
Including
The first and second checkpoint inhibitors may be the same or different.
Method. The method according to claim 1, wherein the oncolytic virus is an adenovirus, a leovirus, a measles virus, a simple herpes virus, a Newcastle disease virus, a Seneca virus, or a vaccinia virus. The method according to claim 2, wherein the oncolytic virus is an adenovirus, a leovirus, a herpes simplex virus, a Newcastle disease virus, or a vaccinia virus. The method according to claim 2, wherein the oncolytic virus is a herpes simplex virus. The method according to claim 4, wherein the herpes simplex virus is a herpes simplex type 1 virus (HSV-1). The HSV1
Lacking the functional ICP34.5 gene,
Lacking the functional ICP47 gene,
The method of claim 5, wherein the method is modified to include a gene encoding a heterologous gene. The method of claim 6, wherein the heterologous gene is a cytokine. The method of claim 7, wherein the cytokine is GM-CSF. The method according to any one of claims 1 to 8, wherein the oncolytic virus is Talimogene Laharparepbeck, RP1, RP2, or RP3. Any of claims 1-9, wherein the first and second checkpoint inhibitors are independently selected from the list comprising CTLA-4 blockers, PD-1 blockers, and PD-L1 blockers. The method described in item 1. 10. The CTLA-4 blocker is an anti-CTLA-4 antibody, the PD-1 blocker is an anti-PD-1 antibody, and the PD-L1 blocker is an anti-PD-L1 antibody, claim 10. the method of. The method of claim 10 or 11, wherein the CTLA-4 blocker is ipilimumab. 10. The method of claim 10 or 11, wherein the PD-1 blocker is selected from a list comprising nivolumab, pembrolizumab, CT-011, AMP-224, and cemiplimab. 10. The method of claim 10 or 11, wherein the PD-L1 blocker is selected from a list comprising atezolizumab, avelumab, durvalumab, and BMS-936559. The cancers are melanoma, breast cancer (eg, triple negative breast cancer), kidney cancer, bladder cancer, colorectal cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, liver cancer, non-melanoma skin cancer, neuroendocrine tumor, T-cell lymphoma ( The method according to any one of claims 1 to 14, wherein the method is, for example, peripheral cancer, or a pediatric solid tumor with unresectable epidermal lesions. 15. The method of claim 15, wherein the cancer is stage 2, 3a, 3b, 3c, 3d or 41a melanoma. A herpes simplex virus that lacks the functional ICP34.5 gene, lacks the functional ICP47 gene, and contains the gene encoding human GM-CSF.
A package insert or label
Administer the oncolytic virus in combination with the first checkpoint inhibitor,
Surgically remove any residual tumor,
A kit that includes a package insert or label with instructions for treating cancer by administering a second checkpoint inhibitor.
The first and second checkpoint inhibitors may be the same or different.
kit. The method of manufacturing the kit according to claim 17. It ’s a cancer treatment method.
Administering an oncolytic virus and
Surgical removal of any residual tumor and
Administering checkpoint inhibitors and
Including, how. 19. The method of claim 19, wherein the oncolytic virus is an adenovirus, a leovirus, a measles virus, a simple herpes virus, a Newcastle disease virus, a Seneca virus, or a vaccinia virus. The method according to claim 20, wherein the oncolytic virus is an adenovirus, a leovirus, a herpes simplex virus, a Newcastle disease virus, or a vaccinia virus. The method of claim 20, wherein the oncolytic virus is a herpes simplex virus. 22. The method of claim 22, wherein the herpes simplex virus is a herpes simplex type 1 virus (HSV-1). The HSV1
Lacking the functional ICP34.5 gene,
Lacking the functional ICP47 gene,
23. The method of claim 23, which has been modified to include a gene encoding a heterologous gene. 24. The method of claim 24, wherein the heterologous gene is a cytokine. 25. The method of claim 25, wherein the cytokine is GM-CSF. The method according to any one of claims 19 to 26, wherein the oncolytic virus is Talimogene Laharparepbeck, RP1, RP2, or RP3. The method of any one of claims 19-27, wherein the checkpoint inhibitor is selected from a list comprising CTLA-4 blockers, PD-1 blockers, and PD-L1 blockers. 28. The CTLA-4 blocker is an anti-CTLA-4 antibody, the PD-1 blocker is an anti-PD-1 antibody, and the PD-L1 blocker is an anti-PD-L1 antibody. the method of. 28. The method of claim 28 or 29, wherein the CTLA-4 blocker is ipilimumab. 28. The method of claim 28 or 29, wherein the PD-1 blocker is selected from a list comprising nivolumab, pembrolizumab, CT-011, AMP-224, and semiprimab. 28. The method of claim 28 or 29, wherein the PD-L1 blocker is selected from a list comprising atezolizumab, avelumab, durvalumab, and BMS-936559. The cancers are melanoma, breast cancer (eg, triple negative breast cancer), kidney cancer, bladder cancer, colorectal cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, liver cancer, non-melanoma skin cancer, neuroendocrine tumor, T-cell lymphoma ( The method according to any one of claims 19 to 32, which is, for example, peripheral) or a pediatric solid tumor with cancer of unknown primary origin or unresectable epidermal lesion. 33. The method of claim 33, wherein the cancer is stage 2, 3a, 3b, 3c, 3d or 41a melanoma. A herpes simplex virus that lacks the functional ICP34.5 gene, lacks the functional ICP47 gene, and contains the gene encoding human GM-CSF.
A package insert or label
Administer oncolytic virus,
Surgically remove any residual tumor,
A package insert or label with instructions for treating cancer by administering a checkpoint inhibitor, and
Including, kit. The method of manufacturing the kit according to claim 35.

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